Approximately one third of AIDS patients develop clinical dementia (AIDS dementias complex, ADC). Many of the clinical symptoms have been attributed to pathologic changes in the subcortical white and grey matter. Nevertheless, radiologic studies and our preliminary pathologic observations suggest that significant cortical atrophy has been overlooked. We propose to characterize the extent and distribution of cortical atrophy in the brain of deceased AIDS patients. We will correlate this atrophy with clinical and radiologic findings in addition to the pathologically more apparent subcortical changes in AIDS patients with and without HIV encephalitis. We will correlate cortical thickness with cell counts to identify which regions demonstrate atrophy and whether there is selective involvement of specific size class neurons. With quantitative immunocytochemistry and western blots we will examine cortical synaptic complexity as a sensitive indicator of cortical damage. Using decreased synaptophysin and increased brain spectrin-like staining as markers of synaptic loss we will compare these measurements with morphologic, clinical and radiologic evidence of cortical atrophy. Because many of these cortical and subcortical changes are occurring in HIV infected brains with limited to no detectable retroviral proteins or nucleic acids, we hypothesize that they are indirect rather than direct affects of infection, perhaps mediated by immune factors. We will examine the role of specific intra-CNS immune factors in mediating cortical and subcortical damage. Unlike other viral encephalitides, brains with HIV encephalitis show little evidence of humoral or cellular immune response. However, there are a variable number of microglia/ macrophages (a preferred target of HIV infection and an important factor in synapse remodeling) in the brains of AIDS patients. Normally MHC class I expression is restricted to endothelial cells while class II expression is not observed except on macrophages, astrocytes and endothelial cells while class II expression is not observed except on macrophages, astrocytes and endothelial cells during an immune response. Since MHC antigens critical in an effective immune response are amplified during viral infections or exposure to cytokines, documentation of their increased presence within the CNS of dementia cases will be a sensitive indicator of viral or immune perturbation. We will characterize the role of macrophage or neural cell (e.g. astrocyte) produced cytokines in mediating CNS damage. Because CNS damage can occur within AIDS patients' brains at a time when o virus is detectable within the brain parenchyma1, we will use commercial ELISA kits to quantify and compare levels of cytokines (IL-1beta, IL-2, IL-6, tumor necrosis factor (TNF), and gamma-interferon) in the serum and CSF from these autopsies. Because these cytokines have a short biological half-life and can be produced within the CNS, we will employ immunoperoxidase and in situ- hybridization on the post-mortem tissue to evaluate the distribution of the cytokines within autopsied brains and compare this in situ distribution with the distribution of neuropathologic changes.